American Journal of Pathology

Successful and timely coronary reperfusion following acute ST-elevation myocardial infarction (STEMI) is standard therapy to salvage ischaemic heart muscle. However, subsequent inflammatory responses within the infarct leads to further loss of viable myocardium. TGFβ1 is a potent anti-inflammatory cytokine released endogenously in response to infection or tissue injury and the goal of this study was to investigate its protective effects when given exogenously following MI. In STEMI patients, we observe a significant correlation (p=0...

Corneal endothelial cells (CEnCs) regulate corneal hydration and maintain tissue transparency through their barrier and pump function. However, these cells exhibit limited regenerative capacity following injury. Currently, corneal transplantation is the only established therapy for restoring endothelial function, and there are no pharmacologic interventions available for restoring endothelial function. In this study, we investigate the efficacy of the neuropeptide α-melanocyte-stimulating hormone (α-MSH) in promoting endothelial regeneration during the critical window between ocular injury and the onset of endothelial decompensation using an established murine model of injury using transcorneal freezing...

Benign prostate hyperplasia (BPH) is caused by the non-malignant enlargement of the transition zone of the prostate gland, leading to lower urinary tract symptoms (LUTS). While current medical treatments are unsatisfactory in many patients, the limited understanding of the mechanisms driving disease progression prevents the development of alternative therapeutic strategies. The probasin-prolactin (Pb-PRL) transgenic mouse recapitulates many histopathological features of human BPH. We here show that these alterations parallel urodynamic disturbance reminiscent of LUTS...

The Wnt/β-catenin pathway represents a promising therapeutic target for mitigating kidney fibrosis. Corin possesses the homologous ligand binding site (Frizzled-cysteine rich domain, Fz-CRD) similar to Frizzled proteins, which act as receptors for Wnt. The Fz-CRD has been found in eight different proteins, all of which, except for corin, are known to bind Wnt and regulate its signal transmission. It is hypothesized that corin may inhibit the Wnt/β-catenin signaling pathway and thereby reduce fibrogenesis...

Endothelial cells (ECs) mediate several biological functions that are relevant to atherosclerosis and coronary artery disease (CAD), regulating an array of vital processes including vascular tone, wound healing, reactive oxygen species, shear stress response, and inflammation. Although it is not yet known which of these functions is linked causally with CAD development and/or progression, genome-wide association studies have implicated more than 400 loci associated with CAD risk, among which several have shown EC-relevant functions...

Loss of hepatic HNF4α expression is frequently observed in end-stage liver disease (ESLD) and associated with loss of vital liver functions and thus increases mortality. Loss of HNF4α expression is mediated by inflammatory cytokines such as TGF-β. However, details of how HNF4α is suppressed are largely unknown to date. This study reports that TGF-β does not directly inhibit HNF4α, but contributes to its transcriptional regulation by SMAD2/3 recruiting acetyltransferase CBP/p300 to the HNF4α promoter...

Control of vascular smooth muscle cell (SMC) gene expression is an essential process for establishing and maintaining lineage identity, contractility, and plasticity. Most mechanisms (epigenetic, transcriptional, and post-transcriptional) implicated in gene regulation occur in the nucleus. Still, intranuclear pathways are directly impacted by modifications in the extracellular environment in conditions of adaptive or maladaptive remodeling. Integration of extracellular, cellular, and genomic information into the nucleus through epigenetic and transcriptional control of genome organization plays a major role in regulating SMC functions and phenotypic transitions during vascular remodeling and diseases...

No abstract text is available yet for this article.

In digital pathology tasks, transformers have achieved state-of-the-art results, surpassing convolutional neural networks (CNNs). However, transformers are usually complex and resource intensive. In this study, we developed a novel and efficient digital pathology classifier called DPSeq, to predict cancer biomarkers through fine-tuning a sequencer architecture integrating horizon and vertical bidirectional long short-term memory networks. Using hematoxylin and eosin-stained histopathologic images of colorectal cancer from two international data sets (The Cancer Genome Atlas and Molecular and Cellular Oncology), the predictive performance of DPSeq was evaluated in a series of experiments...

Mechanisms responsible for the pathogenesis of diabetic retinal disease remain incompletely understood, but likely involve multiple cellular targets, including photoreceptors. Evidence suggests that dysregulated de novo lipogenesis in photoreceptors is a critical early target of diabetes. Following on this observation, the present study aimed to determine whether two interventions shown to improve diabetic retinopathy in mice - pharmacologic visual cycle inhibition and prolonged dark adaptation - reduce photoreceptor anabolic lipid metabolism...

Toxoplasma gondii infection in pregnant women may cause fetal anomalies; however, the underlying mechanisms remain unclear. We investigated whether T. gondii induces pyroptosis in human placental cells and the underlying mechanisms. Human placental trophoblast (BeWo and HTR-8/SVneo) and amniotic (WISH) cells were infected with T. gondii, and then reactive oxygen species (ROS) production, cathepsin B (CatB) release, inflammasome activation, and pyroptosis induction were evaluated. The molecular mechanisms of these effects were investigated by treating the cells with ROS scavengers, a CatB inhibitor, or inflammasome-specific siRNA...

Tumor mutation burden (TMB) is a potential biomarker for evaluating the prognosis and response to immune checkpoint inhibitors, but its costly and time-consuming method of measurement limits its widespread application. This study aimed to identify the TMB-related histopathologic features from hematoxylin and eosin slides and explore their prognostic value in gliomas. We detected the TMB-related features using a graph convolutional neural network from whole-slide images of patients from The Cancer Genome Atlas data set (619 patients), and evaluated the correlation between features and TMB in an external validation set (237 patients)...

Dual-specificity phosphatase 6 (DUSP6) is a specific phosphatase for mitogen-activated protein kinase (MAPK). In this study, we used a high-fat diet (HFD)-induced murine nonalcoholic fatty liver disease model to investigate the role of DUSP6 in this disease. Wild-type (WT) and Dusp6-haploinsufficiency mice developed severe obesity and liver pathology consistent with nonalcoholic fatty liver disease when exposed to HFD. In contrast, Dusp6-knockout (KO) mice completely eliminated these phenotypes. Furthermore, primary hepatocytes isolated from WT mice exposed to palmitic and oleic acids exhibited abundant intracellular lipid accumulation, whereas hepatocytes from Dusp6-KO mice showed minimal lipid accumulation...

In cancer, autophagy has been proposed to play a dual role. In this study, we investigated the role of autophagy in oral carcinogenesis using the model of oral squamous cell carcinoma (OSCC) induced by carcinogen 4-nitroquinoline 1-oxide (4NQO), mimicking molecular and histopathologic aspects of human OSCC. The induction of autophagy by spermidine (SPD) treatment reduced the severity of lesions and the incidence of OSCC in mice exposed to 4NQO. On the other hand, autophagy inhibition by chloroquine treatment had no protection...

The modern taxonomy of disease builds a framework for precision medicine, by which traditional pathological criteria are integrated with clinical and genomic features to define disease entities. Two of the most common subtypes of lymphoma on a worldwide basis are follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). While the BCL2 translocation is the signature lesion of most nodal FL, recent studies have identified significant diversity among follicle-center derived lesions. BCL2-negative FL is a genetically heterogeneous disease that occurs in both nodal and extranodal sites...

Despite the development of antiretroviral therapy (ART), HIV-associated distal sensory polyneuropathy remains prevalent. Using SIV-infected rhesus macaques, this study examined molecular mechanisms of peripheral and central sensitization to infer chronic pain from HIV infection. Previous studies identified atrophy in nociceptive neurons during SIV infection, which was associated with monocyte infiltration into the dorsal root ganglia (DRG). However, the sensory signaling mechanism connecting this pathology to symptoms remains unclear, especially because pain persists after resolution of high viremia and inflammation with ART...

A gradual decline in renal function occurs even in healthy aging individuals. In addition to aging, per se, concurrent metabolic syndrome and hypertension, which are common in the aging population, can induce mitochondrial dysfunction and inflammation, which collectively contribute to age-related kidney dysfunction and disease. This study examined the role of the nuclear hormone receptors, the estrogen-related receptors (ERRs), in regulation of age-related mitochondrial dysfunction and inflammation. The ERRs were decreased in both aging human and mouse kidneys and were preserved in aging mice with lifelong caloric restriction (CR)...

Aging is associated with nonresolving inflammation and tissue dysfunction. Resolvin D2 (RvD2) is a proresolving ligand that acts through the G-protein-coupled receptor called GPR18. Unbiased RNA sequencing revealed increased Gpr18 expression in macrophages from old mice, and in livers from elderly humans, which was associated with increased steatosis and fibrosis in middle-aged (MA) and old mice. MA mice that lack GPR18 on myeloid cells had exacerbated steatosis and hepatic fibrosis, which was associated with a decline in Mac2+ macrophages...

No abstract text is available yet for this article.

No abstract text is available yet for this article.